Phase III Randomized Trial of Isatuximab Addition to Lenalidomide, Bortezomib, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients
- Trial ID
- 2024-513464-26-00
- Protocol
- GMMG-HD7
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of this randomized phase III trial are to evaluate the efficacy of the induction regimen and maintenance strategies in patients with newly diagnosed **multiple myeloma**. Specifically, the study aims to compare the induction regimen (IA vs IB) regarding **minimal residual disease** (MRD) negativity after induction, assessed by flow cytometry with a sensitivity of 1e-5. Additionally, it seeks to compare the maintenance strategies (arms IIA vs IIB) in terms of **progression-free survival** (PFS), defined as the time from the second randomization (prior to maintenance therapy) to progression or death from any cause, whichever occurs first. These objectives are clinically relevant as they address the potential for improved disease control and survival outcomes in multiple myeloma patients.
The secondary objectives include: - Comparing the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding PFS from the first randomization to progression or death. - Assessing the treatment effect of the induction phase on PFS by comparing overall IA to IB and specifically IA-IIA to IB-IIA. - Comparing treatment arms regarding overall survival (OS) from the first and second randomizations, complete response (CR) rates, MRD negativity, sustained MRD negativity, best response to treatment, PFS after the next line of therapy, and toxicity during induction and maintenance. - Evaluating quality of life using EORTC-QLQC30, EORTC-QLQMY20, and EQ-5D-5L questionnaires. - Characterizing the pharmacokinetics of isatuximab in combination with lenalidomide/bortezomib/dexamethasone or lenalidomide/dexamethasone in this patient population.
Participants
The clinical trial focuses on **Multiple Myeloma** and includes participants aged 18 to 70 years, encompassing both male and female subjects. The study population is characterized by individuals with a confirmed diagnosis of untreated multiple myeloma requiring systemic therapy, who are eligible for high-dose therapy and autologous stem cell transplantation. Participants are required to have measurable disease and a WHO performance status of 0-2. The trial does not involve a vulnerable population. Lifestyle considerations include adherence to a lenalidomide pregnancy prevention plan, with specific requirements for contraception and restrictions on blood donation and drug sharing. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of adding **isatuximab** to a regimen of **lenalidomide**, **bortezomib**, and **dexamethasone** in patients with newly diagnosed **multiple myeloma**. The trial aims to assess two primary endpoints: minimal residual disease (MRD) negativity after induction and progression-free survival (PFS) during maintenance therapy. The study is expected to run from October 2018 to March 2027, with participant involvement lasting up to 41 months, depending on individual response and treatment tolerability.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and disease characteristics. Following successful screening, participants will be randomized into treatment arms and commence the induction phase. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and compliance with the study protocol. The end-of-study visit will occur after the completion of the maintenance phase or upon early termination.
Early termination from the study may occur due to disease progression, unacceptable toxicity, withdrawal of consent, or any condition that, in the investigator's opinion, warrants discontinuation. Participants are required to adhere to specific safety measures, including the use of contraception and abstaining from blood donation while on **lenalidomide**. The trial's design ensures rigorous monitoring and data collection to achieve its objectives, contributing valuable insights into the treatment of multiple myeloma.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their efficacy in patients with newly diagnosed **multiple myeloma**. The primary experimental medication is **Lenalidomide**, which is provided in hard capsule form. It is available in dosages of 5 mg, 10 mg, 15 mg, and 25 mg. The maximum daily dose is 25 mg, with a total maximum dose of 18,060 mg over a treatment period of 41 weeks. Lenalidomide is administered orally, and its active substance is of chemical origin, produced by Celgene Corporation.
Another experimental medication used in the trial is **Isatuximab**, a solution for infusion. The maximum daily dose is 10 mg/kg, with a total maximum dose of 550 mg/kg over the same 41-week period. Isatuximab is administered via infusion and is a protein-based substance developed by Sanofi Aventis Recherche et Développement.
**Bortezomib** is included as a non-experimental treatment in the study. It is provided as a powder for solution for injection, with a maximum daily dose of 1.3 mg/m² and a total maximum dose of 31.2 mg/m² over a 3-week period. Bortezomib is administered subcutaneously and is of chemical origin, manufactured by Janssen-Cilag International NV.
Additionally, **Dexamethasone** is used as a comparator treatment. It is available in tablet form, with a maximum daily dose of 20 mg and a total maximum dose of 1,100 mg over a 154-week period. Dexamethasone is administered orally and is also of chemical origin.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the benefit of adding Isatuximab to the Lenalidomide, Bortezomib, and Dexamethasone regimen, with a focus on minimal residual disease negativity and progression-free survival.
Efficacy
The efficacy of the clinical trial will be assessed using two primary endpoints: **minimal residual disease (MRD)** negativity after induction and progression-free survival (PFS). MRD negativity will be evaluated by flow cytometry with a sensitivity of 1e-5, measuring the proportion of patients achieving negative MRD status post-induction. PFS is defined as the duration from the second randomization, prior to maintenance therapy, to either disease progression or death from any cause, whichever occurs first.
Secondary endpoints include PFS from the first randomization to progression or death, overall survival (OS) from both first and second randomizations to death from any cause, and complete response (CR) rates. CR rates will be adjusted for isatuximab interference in immunofixation tests. Additional secondary endpoints involve MRD negativity after high-dose therapy and during maintenance, sustained MRD-negativity for periods of 6 and 12 months, best response to treatment, PFS after the next line of therapy (PFS 2), and quality of life assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients meeting all of the following criteria will be considered for admission to the trial:
- Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy.
- Patient is eligible for high dose therapy and autologous stem cell transplantation.
- Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:34 • Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l) • Urine light-chain (M-protein) of ≥ 200 mg/24 hours • Serum FLC assay: involved sFLC level ≥ 10 mg/dl and abnormal sFLC ratio
- Age 18 - 70 years inclusive
- WHO performance status 0-2
- Negative pregnancy test at inclusion (females of childbearing potential).
- All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy.
- All patients must • agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy • agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist
- Ability of patient to understand character and individual consequences of the clinical trial.
- Provide written informed consent (must be available before enrolment in the trial).
Exclusion Criteria
- Patients presenting with any of the following criteria will not be included in the trial:
- Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents.
- Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
- Plasma cell leukemia
- Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression or benign diseases, such as nonmalignant thyroid diseases. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion.
- Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40%.
- Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert’s disease), unless related to myeloma.
- Patients with active or history of hepatitis B or C (Prior hepatitis B may be acceptable if an adequate prophylaxis is being implemented during the course of the study.)
- HIV positivity
- Patients with active, uncontrolled infections
- Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min)
- Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0)
- Patients with a history of active malignancy during the past 5 years with the exception of the following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy (A history of an early stage malignancy during the past 5 years may be acceptable. In this case the GMMG study office has to be consulted prior to study inclusion.)
- Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
- Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
- Platelet count < 75 x 10^9/l (Platelet transfusions are not permitted to improve platelet count prior to study inclusion.)
- Haemoglobin ≤ 8.0 g/dl, unless related to myeloma
- Absolute neutrophil count (ANC) < 1.0 x 10^9/l (the use of colony stimulating factors within 14 days before the test is not allowed)
- Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l)
- Unable or unwilling to undergo thromboprophylaxis
- Pregnancy and lactation
- Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.
- Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 23 Oct 2018 | 662 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lenalidomide | Test | CAPSULE, HARD | ORAL | 25 | 41 | PRD10089707 |
Lenalidomide | Test | CAPSULE, HARD | ORAL | 25 | 41 | PRD10089705 |
Isatuximab | Test | SOLUTION FOR INFUSION | INFUSION | 10 | 41 | PRD10653334 |
Lenalidomide | Test | CAPSULE, HARD | ORAL | 25 | 41 | PRD10089704 |
VELCADE 3.5 mg powder for solution for injection | Other | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 1.3 | 3 | PRD3349073 |
Lenalidomide | Test | CAPSULE, HARD | ORAL | 25 | 41 | PRD10089706 |
DEXAMETHASONE | Other | — | ORAL | 20 | 154 | SUB07017MIG |